PJP is a rare but potentially life-threatening infection seen in immunocompromised patients. We sought to determine the risk factors for acquiring Pneumocystis jirovecii pneumonia (PJP) in pediatric solid organ transplant (SOT) recipients and the associated morbidity, mortality, and hospital resource use.

Patients ≤ 18 years who underwent solid organ transplantation from 1/1/2003-12/31/2022 at hospitals utilizing the Pediatric Health Information System database were identified. Their transplant hospitalization and subsequent hospitalizations were analyzed. Risk factors for PJP infections were evaluated using Cox survival analysis adjusted for confounders.

Among the total 18 104 SOT recipients, 59 (0.3%) were admitted with PJP during the study period, of which 17% were considered breakthrough infections. The majority of PJP infections occurred early post-transplant, with a median time to infection of 1.2 years (interquartile range [IQR] 0.4-1.9 years) post-transplant. In adjusted analyses, there was an increased risk of PJP in patients who underwent heart transplantation and patients who were < 1 year of age at the time of transplant. The median length of stay for a PJP hospitalization was 16 days (IQR 7-31 days) with a median adjusted total cost of $57 142 (IQR $25 009-$154 251). The overall mortality rate was 9%.

In the current era, PJP remains a rare post-transplant complication in pediatric SOT patients. PJP infections occurred more frequently among infants and heart transplant recipients, and were associated with significant morbidity, mortality, and costs. Further studies are needed to identify patient-specific risk factors for PJP among pediatric SOT recipients and define indications for extended PJP prophylaxis or reinitiation.

To evaluate the prognostic value of SII and LMR in predicting hearing recovery outcomes in profound SSHL cases.

The relationships between inflammatory markers and hearing outcomes were assessed using univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive accuracy of SII and LMR for recovery outcomes.

The study revealed that SII and LMR were linked to hearing recovery in profound SSHL. Cases in the complete recovery group had significantly lower SII (806.57 ± 217.26) and higher LMR (2.14 ± 0.94) compared to those in the partial and no recovery groups (P < 0.001 for both). Multivariate logistic regression identified Tbil, SII, and LMR as independent predictors of recovery outcomes. Higher SII and lower LMR were significantly associated with poor recovery, while lower SII and higher LMR predicted better recovery. ROC curve analysis showed that SII and LMR had moderate predictive power for partial recovery (AUC: 0.668 for SII, 0.696 for LMR) and excellent predictive power for no recovery (AUC: 0.804 for SII, 0.819 for LMR). The combination of SII and LMR further enhanced predictive accuracy (AUC: 0.879 for no recovery).

SII and LMR are valuable biomarkers for predicting recovery outcomes in cases with profound SSHL. Elevated SII and reduced LMR are associated with poor recovery, while lower SII and higher LMR suggest a favorable prognosis. The combined use of these markers improves the accuracy of prognosis prediction and could guide clinical management in SSHL cases.

Systemic autoinflammatory diseases are rare conditions resulting from dysregulation of the innate immune system, culminating in repetitive bouts of systemic inflammation without the presence of external or self-antigens. Most systemic autoinflammatory diseases are associated with mutations in genes affecting the innate immune response. Tumor necrosis factor is a central player in the pathogenesis of numerous chronic inflammatory disorders, and anti-tumor necrosis factor therapy is widely used in the clinical management of systemic autoinflammatory diseases. Tumor necrosis factor inhibitors block the interaction of tumor necrosis factor with its 2 receptors, tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2. These inhibitors primarily target soluble tumor necrosis factor, which mainly binds to tumor necrosis factor receptor 1, exerting anti-inflammatory effects. Interestingly, tumor necrosis factor inhibitors also affect transmembrane tumor necrosis factor, which engages tumor necrosis factor receptor 2 to initiate reverse signaling. This reverse signaling can activate innate immune cells, prevent apoptosis, or paradoxically inhibit the production of pro-inflammatory cytokines. Tumor necrosis factor inhibitors also promote the release of soluble tumor necrosis factor receptor 2, which neutralizes circulating tumor necrosis factor. Some agents targeting tumor necrosis factor receptor 2 can even act as agonists, triggering reverse signaling by binding to transmembrane tumor necrosis factor. While effective, prolonged use of tumor necrosis factor inhibitors may cause significant side effects due to the widespread expression and pleiotropic functions of tumor necrosis factor receptors. A more thorough understanding of the mechanisms underlying the action of tumor necrosis factor inhibitors is required to develop a more effective and safer treatment for systemic autoinflammatory diseases. This article reviews current studies on the role of the innate immune system in systemic autoinflammatory disease pathogenesis, the impact of anti-tumor necrosis factor therapy on innate immune cells, and perspectives on developing improved agents targeting tumor necrosis factor or its receptors.

Immune memory is a hallmark of the adaptive immune system. However, recent research reveals that innate immune cells also retain memory of prior pathogen exposure that prompts enhanced responses to subsequent infections. This phenomenon is termed "innate immune memory" or "trained immunity." Notably, remodeling of cellular metabolism, which closely links to epigenetic reprograming, is a prominent feature of innate immune memory. Adaptations in glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, glutaminolysis, and lipid synthesis pathways are critical for establishing innate immune memory. This review provides an overview of the current understanding of how metabolic adaptations drive innate immune memory. This understanding is fundamental to understanding innate immune system functions and advancing therapies against infectious diseases.

Antiviral restriction factors such as MxA (myxovirus resistance protein A) inhibit many viruses. Viral escape drives restriction factors to evolve rapidly at virus-binding interfaces to regain defense. Here, we explore how antiviral proteins balance restricting many viruses with evolving specificity against individual viruses. Human MxA uses its rapidly evolving loop L4 as the specificity determinant for orthomyxoviruses such as thogotovirus (THOV) and influenza (IAV). Previous combinatorial mutagenesis of rapidly evolving residues in human MxA loop L4 identified THOV "super-restrictors" and suggested an antiviral breadth-specificity trade-off. Using a modified combinatorial mutagenesis strategy, we find super-restrictor MxA variants specific to H5N1 IAV. A single L4 residue underlies the MxA breadth-specificity trade-off. However, rare "generalist" super-restrictors or a heterozygous combination of more common "specialist" super-restrictors can overcome the breadth-specificity trade-off. Our findings suggest that at least two strategies enable restriction factors such as MxA to increase their restriction of diverse viruses to overcome breadth-specificity trade-offs, which might be pervasive in host-virus conflicts.

Pathogen reinfections occur widely, but the extent to which reinfected hosts contribute to ongoing transmission is often unknown despite its implications for host-pathogen dynamics. House finches (Haemorhous mexicanus) acquire partial protection from initial exposure to the bacterial pathogen Mycoplasma gallisepticum (MG), with hosts readily reinfected with homologous or heterologous strains on short timescales. However, the extent to which reinfected hosts contribute to MG transmission has not been tested. We used three pathogen priming treatments-none, intermediate (repeated low-dose priming), or high (single high-dose priming)-to test how prior pathogen priming alters the likelihood of transmission to a cagemate during index bird reinfection with a homologous or heterologous MG strain. Relative to unprimed control hosts, the highest priming level strongly reduced maximum pathogen loads and transmission success of index birds during reinfections. Reinfections with the heterologous strain, previously shown to be more virulent and transmissible than the homologous strain used, resulted in higher pathogen loads within high-primed index birds and showed higher overall transmission success regardless of host priming treatment. This suggests that inherent differences in strain transmissibility are maintained in primed hosts, leading to the potential for ongoing transmission during reinfections. Finally, among individuals, transmission was most likely from hosts harboring higher within-host pathogen loads. However, associations between disease severity and transmission probability were dependent on a given bird's priming treatment. Overall, our results indicate that reinfections can result in ongoing transmission, particularly where reinfections result from a highly transmissible strain, with potential implications for virulence evolution.IMPORTANCEAs COVID-19 dramatically illustrated, humans and other animals can become infected with the same pathogen multiple times. Because individuals already have defenses against pathogens that their immune systems encountered before, reinfections are likely less contagious to others, but this is rarely directly tested. We used a songbird species and two strains of its common bacterial pathogen to study how contagious hosts are when their immune systems have some degree of prior experience with a pathogen. We found that reinfected hosts are not as contagious as initially infected ones. However, the more transmissible of the two strains, which also causes more harm to its hosts, was able to multiply more readily than the other strain within reinfected hosts and was more contagious in both reinfected and first-infected hosts. This suggests that reinfections might favor more harmful pathogen strains that are better able to overcome immune defenses.

BCG is the oldest vaccine in continuous use. While current intradermal vaccination regimens confer limited protection outside the context of pediatric extrapulmonary tuberculosis (TB), promising new data indicate that when administered mucosally or intravenously at a higher dose, BCG can induce sterilizing immunity against pulmonary TB in nonhuman primates. BCG is also known to promote nonspecific host resistance against a variety of unrelated infections and is a standard immunotherapy for bladder cancer, suggesting that this innate immune function may contribute to its protective role against TB. Here, we propose that both the mycobacterial-specific and off-target effects of BCG depend on the interplay of adaptive and innate cells and the cytokines they produce, and that the elucidation of this interaction should be a major strategy in the development of more effective BCG-based vaccines and immunotherapies.

There has been an increasing effort to understand the memory responses of a complex interplay among innate, adaptive, and structural cells in peripheral organs and bone marrow. Trained immunity is coined as the de facto memory of innate immune cells and their progenitors. These cells acquire epigenetic modifications and shift their metabolism to equip an imprinted signature to a persistent fast-responsive functional state. Recent studies highlight the contribution of noncoding RNAs and modulation of chromatin structures in establishing this epigenetic readiness for potential immune perturbations. In this review, we discuss recent studies that highlight trained immunity-mediated memory responses emerging intrinsically in innate immune cells and as a complex interplay with other cells at the organ level. Lastly, we survey epigenetic contributors to trained immunity phenotypes-specifically, a recently discovered regulatory circuit coordinating the regulation of a key driver of trained immunity.

The production of specific antibodies occurs in response to pathogens, whether encountered naturally or introduced through vaccination, serving as markers of immunity. As novel vaccines are developed and deployed, especially in response to emerging infectious diseases, the ability to distinguish between vaccine-induced and infection-induced antibodies becomes increasingly important. Vaccines are designed to mimic this natural infection process without causing the disease itself. Serological assays are critical tools in immunology, enabling researchers and clinicians to differentiate between antibodies produced by vaccination and those generated by natural infection. By understanding whether an individual's antibodies are the result of previous infection or vaccination, healthcare providers can modify booster recommendations more effectively. It also plays an important role in identifying people with hybrid immunity and in assessing the effectiveness of vaccination campaigns.

Tissue-resident memory T (TRM) cells are a distinct subset of memory T cells that persist in non-lymphoid tissues, providing localized and rapid immune responses to infection and malignancy. Unlike circulating memory T cells, TRM cells have unique homing and functional characteristics that are shaped by the tissue microenvironment. In the gut, TRM cells play a pivotal role in maintaining mucosal immunity, exhibiting phenotypic and functional heterogeneity in different intestinal compartments and in response to aging and pathological conditions.

This review aims to systematically examine the definition, spatial heterogeneity and functional roles of intestinal TRM (iTRM) cells. It highlights their contributions to physiological immunity, their involvement in pathological processes such as inflammatory bowel disease (IBD) and colorectal cancer (CRC), and their age-related dynamics. The review also explores emerging therapeutic implications of modulating iTRM cells for intestinal health and disease management. KEY SCIENTIFIC CONCEPTS OF REVIEW: iTRM cells are defined by surface markers like CD69 and CD103, transcriptional regulators such as Hobit, Runx3, Blimp-1, as well as cytokine signals including TGF-β, IFN-β, IL-12. They exhibit spatial and functional heterogeneity across intestinal layers (epithelium versus lamina propria) and regions (small intestine versus colon). In IBD, iTRM cells play a dual role, contributing to both inflammation and tissue repair, whereas in CRC, specific subsets of iTRM cells (e.g., CD8+ CD103+ CD39+) are associated with enhanced antitumor immunity. Aging impacts iTRM functionality, with shifts in the CD4+/CD8+ ratio and reduced cytokine production in elderly individuals. Insights into the metabolic, transcriptional, and environmental regulation of iTRM cells provide avenues for targeted therapies in intestinal diseases, cancer immunotherapy, and interventions to delay intestinal aging.

Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy. Traditional chemotherapy methods not only bring serious side effects, but also lead to high recurrence rate and drug resistance in some patients. However, as an emerging therapeutic strategy, immunotherapy has shown great potential in the field of AML treatment in recent years. At present, common immunotherapy methods for AML include monoclonal antibodies, CAR-T cell therapy, and immune checkpoint inhibitors. With the deepening of research and technological progress, especially the application of nanotechnology in medicine, new immunotherapy is expected to become one of the important means for the treatment of acute myeloid leukemia in the future.

Vaccination is an effective strategy for preventing infectious diseases. Subunit vaccines offer more precise targeting and safer protection compared with traditional inactivated virus vaccines. However, due to their poor immunogenicity, subunit vaccines necessitate the use of adjuvants to stimulate the immune system. Adjuvants have long been incorporated into vaccines to enhance the body's immune response, allowing for reduced dosage and lower production costs. Despite the development of numerous vaccine adjuvants, few exhibit the necessary potency and low toxicity for clinical use, often due to limited efficacy or adverse side effects. This underscores the urgent need for novel human vaccine adjuvants that are safe, effective, and cost-efficient. Recent studies have identified certain natural polysaccharides as promising human vaccine adjuvants due to their immunostimulatory properties, low toxicity, and high safety profiles, which enhance both humoral and cellular immunity. These natural polysaccharides are primarily derived from traditional Chinese medicine (TCM) plants, bacteria, and yeast. This review comprehensively analyzes several promising polysaccharide adjuvants, discussing their clinical applications, market potential, and immunoregulatory activities. In summary, the future prospects of polysaccharides provide valuable insights for the application and development of vaccine adjuvants.

The mitochondrial antiviral signaling protein (MAVS) is a pivotal adaptor in the antiviral innate immune signaling pathway and plays a crucial role in the activation of antiviral defences. This comprehensive review delves into the multifaceted functions of MAVS, spanning from its integral role in the RIG-I-like receptor (RLR) pathway to its emerging roles in tumor biology and autoimmune diseases. We discuss the structural and functional aspects of MAVS, its activation mechanisms, and the intricate regulatory networks that govern its activity. The potential of MAVS as a therapeutic target has been explored, highlighting its promise in personalized cancer therapy and developing combination treatment strategies. Additionally, we compare it with the STING signaling pathway and discuss the synergistic potential of targeting both pathways in immunotherapy. Our review underscores the importance of MAVS in maintaining immune homeostasis and its implications for a broad spectrum of diseases, offering new avenues for therapeutic intervention.

The role of mesenchymal cells during respiratory infection is not well defined, including whether, which, and how the different types of mesenchymal cells respond. We collected all mesenchymal cells from lung single-cell suspensions of mice that were naive (after receiving only saline vehicle), pneumonic (after intratracheal instillation of pneumococcus 24 hours previously), or resolved from infection (after nonlethal pneumococcal infections 6 weeks previously) and performed single-cell RNA sequencing. Cells clustered into 5 well-separated groups based on their transcriptomes: matrix fibroblasts, myofibroblasts, pericytes, smooth muscle cells, and mesothelial cells. Fibroblasts were the most abundant and could be further segregated into Pdgfra+Npnt+Ces1d+Col13a1+ alveolar fibroblasts and Cd9+Pi16+Sca1+Col14a1+ adventitial fibroblasts. The cells from naive and resolved groups overlapped in dimension reduction plots, suggesting the mesenchymal cells returned to baseline transcriptomes after resolution. During pneumonia, all mesenchymal cells responded with altered transcriptomes, revealing a core response that had been conserved across cell types as well as distinct mesenchymal cell type-specific responses. The different subsets of fibroblasts induced similar gene sets, but the alveolar fibroblasts responded more strongly than the adventitial fibroblasts. These data demonstrated diverse and specialized immune activities of lung mesenchymal cells during pneumonia.

Pathogens can not only cause infectious diseases, immune system diseases, and chronic diseases, but also serve as potential triggers or initiators for certain tumors. They directly or indirectly damage human health and are one of the leading causes of global deaths. Small ubiquitin-like modifier (SUMO) modification, a type of protein post-translational modification (PTM) that occurs when SUMO groups bond covalently to particular lysine residues on substrate proteins, plays a crucial role in both innate and adaptive immunologic responses, as well as pathogen-host immune system crosstalk. SUMOylation participates in the host's defense against pathogens by regulating immune responses, while numerically vast and taxonomically diverse pathogens have evolved to exploit the cellular SUMO modification system to break through innate defenses. Here, we describe the characteristics and multiple functions of SUMOylation as a pivotal PTM mechanism, the tactics employed by various pathogens to counteract the immune system through targeting host SUMOylation, and the character of the SUMOylation system in the fight between pathogens and the host immune system. We have also included a summary of the potential anti-pathogen SUMO enzyme inhibitors. This review serves as a reference for basic research and clinical practice in the diagnosis, prognosis, and treatment of pathogenic microorganism-caused disorders.

Disease tolerance is an evolutionarily conserved host defense strategy that preserves tissue integrity and physiology without affecting pathogen load. Unlike host resistance, the mechanisms underlying disease tolerance remain poorly understood. In the present study, we investigated whether an adjuvant (β-glucan) can reprogram innate immunity to provide protection against influenza A virus (IAV) infection. β-Glucan treatment reduces the morbidity and mortality against IAV infection, independent of host resistance. The enhanced survival is the result of increased recruitment of neutrophils via RoRγt+ T cells in the lung tissue. β-Glucan treatment promotes granulopoiesis in a type 1 interferon-dependent manner that leads to the generation of a unique subset of immature neutrophils utilizing a mitochondrial oxidative metabolism and producing interleukin-10. Collectively, our data indicate that β-glucan reprograms hematopoietic stem cells to generate neutrophils with a new 'regulatory' function, which is required for promoting disease tolerance and maintaining lung tissue integrity against viral infection.

The mammalian adipose tissue (AT) plays a key role in regulating immune function and anti-infective protection to maintain tissue regional homeostasis. However, it is still unclear whether there are differences in the participation of AT in primary and secondary immune response, and whether avian AT has the similar immune function characteristics to mammals. In this study, we used Newcastle disease virus (NDV) attenuated vaccine to induce primary and secondary immune response in chickens, and the changes of the key regulatory gene NR4A3 (nuclear receptor subfamily 4 group A member 3) of T cells activation and its targeted miR-20a-5p were detected by quantitative real-time PCR (qRT-PCR). The results showed that NR4A3 actively participated in immune response of AT, and showed significant differences in expression activities between the two immune processes. "MiR-20a-5p/NR4A3" pathway was a potential molecular mechanism involved in the regulation of immune function in AT. Moreover, AT responded differently to the primary and secondary immune response possibly through the different patterns of source, apoptosis and migration for lymphocytes (such as CD8β+ T cells). This study can provide directional guidance for further studying immune functions of avian AT.

A decade after the term 'trained immunity' (TRIM) was coined to reflect the long-lasting hyper-responsiveness of innate immune cells with an epigenetically imprinted 'memory' of earlier stimuli, our understanding has broadened to include the potential implications of TRIM in health and disease. Here, after summarizing the well-documented beneficial effects of TRIM against infections, we discuss emerging evidence that TRIM is also a major underlying mechanism in chronic inflammation-related disorders such as periodontitis, rheumatoid arthritis and cardiovascular disease. Furthermore, mounting evidence indicates that the induction of TRIM by certain agonists confers protective antitumour responses. Although the mechanisms underlying TRIM require further study, the current knowledge enables the experimental development of innovative therapeutic approaches to stimulate or inhibit TRIM in a context-appropriate manner, such as the stimulation of TRIM in cancer or its inhibition in inflammatory disorders.

Globally, with improvements in general hygiene, the incidence of early childhood (0-4Y-olds/<5Y-olds) brain and central nervous system (BCNS) cancers is increasing. Although immunological underpinning is suspected, the identification of protective variables for the majority of BCNS cancer cases remains elusive. Extant hypotheses suggest a role for progressively diminishing exposure to common microbes/pathogens in the rise of childhood cancers in industrialized countries with improved hygiene. Natural exposure to common microbes/pathogens and childhood vaccinations help train the developing immune system of children to respond appropriately to future infections and maintain a healthy immune system. Considering the established role of childhood vaccinations in augmenting immunity, including "trained immunity," their protective role in pediatric cancers may be surmised. However, a lack of definitive theoretical and practical frameworks to explain conflicting observations has impaired progress. When we analyze the epidemiological data of European region countries with different childhood vaccination policies but more similar socioeconomic conditions, access to medical services, and genetic makeup as compared to other parts of the world, the coverage of seven major childhood (0-1Y-olds) vaccines does not significantly associate with BCNS cancer incidences in the same cohort of 0-4Y-olds (2020). However, interestingly, prevailing tuberculin immunoreactivity, a surrogate for the existence of heterologous cell-mediated immunity resulting from exposure to Mycobacterium spp., including Bacille Calmette-Guérin (BCG) vaccination, for these populations, is found consistently negatively correlated with the BCNS cancer incidence in 0-4Y-olds for countries mandating neonatal BCG vaccination [r(24): -0.7226, p-value:<0.0001]. Seemingly, neonatal immune-system priming by BCG and boosting by exposure to environmental Mycobacterium spp. appear protective in 0-4Y-olds. Exploration of BCNS cancer incidence and prevailing immune correlates in matched cohorts, along with prospective randomized controlled trials, may be warranted to conclusively ascertain the impact of childhood vaccinations and boosters (including natural exposure) on early childhood BCNS cancer incidence.

An effective vaccination policy must be implemented to prevent foot-and-mouth disease (FMD). However, the currently used vaccines for FMD have several limitations, including induction of humoral rather than cellular immune responses.

To overcome these shortcomings, we assessed the efficacy of levamisole, a small-molecule immunomodulator, as an adjuvant for the FMD vaccine. We conducted in vitro studies using murine peritoneal exudate cells (PECs) and porcine peripheral blood mononuclear cells (PBMCs) and in vivo studies using mice (experimental animals) and pigs (target animals). We evaluated levamisole-mediated modulation of the innate and adaptive immune responses; early, mid-term, and long-term immune-inducing effects; modes of action; and host defense against viral infection.

Levamisole treatment promoted IFNγ secretion in murine PECs and porcine PBMCs. Additionally, it induced robust and long-lasting immune responses by eliciting high antibody titers and high virus-neutralizing antibody titers. By activating downstream signaling pathways of various pattern-recognition receptors, levamisole stimulated the expression of multiple cytokines and costimulatory molecules. Owing to these immunostimulatory effects, levamisole elicited host defense against viral infections in pigs. Our findings demonstrate the potential of levamisole as an immunostimulatory agent.

The results also indicate that levamisole, as an adjuvant for animal vaccines, can elicit robust innate and adaptive immune responses, thereby enhancing host defense against viral infections. This study provides a promising approach for the development of improved FMD vaccine strategies in the future.

Periodontitis is one of the most common oral diseases. It is generally treated by non-surgical and/or surgical therapy with adjunctive approaches for prevention and control. The current understanding of the pathogenesis of periodontitis has unraveled the importance of the inflammatory and immune reactions to combat periodontitis whose etiology is an overlap of microbial, genetic, and environmental factors in a susceptible host. Based on this premise, many therapeutic modalities have been investigated or attempted to resolve this inflammatory disease. Amongst these, nanomedicine has been shown to have therapeutic applications in periodontitis, especially focused on immunomodulation because periodontitis is characterized by over-reactive immune response. This mini-review explores the potential of nanosystems in treating periodontitis by providing an overview of the research efforts in this field of therapeutics. The unique physicochemical and targeting properties of nanosystems seem to be potentially effective platforms for treating periodontitis.

Immune stimuli are able to trigger long-term protective effects through mechanisms of trained immunity, which has attracted increasing attention. Although the existence of trained immunity has evidenced in teleost fish, while there were no such reports in pufferfish (Takifugu obscurus) so far. Therefore, the present study aimed to evaluate the induction of β-glucan and mannan on the trained immunity and their protective efficacy against Vibrio harveyi re-stimulation in pufferfish. β-glucan and mannan induction of trained immunity in head-kidney primary leukocytes is accompanied by a strong increase in immediate ROS burst, cumulative NO production and lactate concentrations after V. harveyi re-stimulation. In addition, β-glucan and mannan-treated pufferfish exhibited reduced bacterial loads in multiple tissues, a rapid and long-term elevated inflammatory response in head kidney during secondary V. harveyi infection. Notably, immune receptors dectin-1 and dectin-2, and cytokines tnfsf14 and il-1β exhibited comparatively upregulation to the β-glucan training, while NK-lysin and faslg showed stronger response to the mannan training post V. harveyi stimulation, implying the different signaling pathway activated post β-glucan and mannan training. Subsequent markers for immune training including abundance of genes encoding glycolytic enzymes (hk1, pfkla, and ldha) and transcription factors (mtor and hif-1α), as well as increased acetylation levels were elevated in the β-glucan and mannan trained pufferfish, depicting heightened glycolysis following β-glucan and mannan training. These results collectively demonstrated that β-glucan and mannan both induced protective responses against V. harveyi infection probably through mediating distinct signaling pathway in pufferfish, and studies are underway to harness its potential applicability for prime and boost vaccination strategies.

This study employs knowledge mapping and bibliometric techniques to analyze the research landscape of trained immunity over the past 20 years and to identify current research hotspots and future development directions. The literature related to trained immunity was searched from the Web of Science Core Collection database, spanning 2004 to 2023. VOSViewer, CiteSpace and Bibliometrix were used for the knowledge mapping analysis. The foremost research institutions are Radboud University Nijmegen, University of Bonn, and Harvard University. Professor Netea MG of Radboud University Nijmegen has published the greatest number of articles. The current research focus encompasses immune memory, nonspecific effects, epigenetics, metabolic reprogramming, BCG vaccine, and the development of trained immunity-based vaccines. It is likely that research on trained immunity-based vaccines will become a major focus in the development of new vaccines in the future. It would be advantageous to observe a greater number of prospective clinical studies with robust evidence.

Immunotherapy, particularly that based on blocking checkpoint proteins in many tumors, including melanoma, Merkel cell carcinoma, non-small cell lung cancer (NSCLC), triple-negative breast (TNB cancer), renal cancer, and gastrointestinal and endometrial neoplasms, is a therapeutic alternative to chemotherapy. Immune checkpoint inhibitor (ICI)-based therapies have the potential to target different pathways leading to the destruction of cancer cells. Although ICIs are an effective treatment strategy for patients with highly immune-infiltrated cancers, the development of different adverse effects including cutaneous adverse effects during and after the treatment with ICIs is common. ICI-associated cutaneous adverse effects include mostly inflammatory and bullous dermatoses, as well as severe cutaneous side reactions such as rash or inflammatory dermatitis encompassing erythema multiforme; lichenoid, eczematous, psoriasiform, and morbilliform lesions; and palmoplantar erythrodysesthesia. The development of immunotherapy-related adverse effects is a consequence of ICIs' unique molecular action that is mainly mediated by the activation of cytotoxic CD4+/CD8+ T cells. ICI-associated cutaneous disorders are the most prevalent effects induced in response to anti-programmed cell death 1 (PD-1), anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and anti-programmed cell death ligand 1 (PD-L1) agents. Herein, we will elucidate the mechanisms regulating the occurrence of cutaneous adverse effects following treatment with ICIs.

Agriculture dust contains many organic immunogenic compounds, and organic dust exposure is strongly associated with the development of immune-mediated chronic pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Chronic organic dust exposure from agriculture sources induces chronic lung inflammatory diseases and organic dust exposure has recently been linked to an increased risk of developing dementia. The cytokine interleukin-22 (IL-22) has been established as an important mediator in the resolution and repair of lung tissues. The omega-3 fatty acid metabolite aspirin-triggered Resolvin D1 (AT-RvD1) has shown efficacy in modulating the immune response in both pulmonary and neurological inflammation but has not been explored as a therapeutic in organic dust exposure-induced neuroinflammation. Investigating the link between IL-22 and AT-RvD1 may help in developing effective therapies for these immune-mediated diseases. We aimed to investigate the link between organic dust exposure and neuroinflammation, the role of IL-22 in the pulmonary and neurological immune response to organic dust exposure, and the immune-modulating therapeutic applications of AT-RvD1 in an IL-22 knock-out mouse model of organic dust exposure. C57BL/6J (WT) and IL-22 knock-out (KO) mice were repetitively exposed to aqueous agriculture organic dust extract (DE) 5 days per week for 3 weeks (15 total instillations) and treated with AT-RvD1 either once per week (3 total injections) or 5 times per week (15 total injections) for 3 weeks and allowed to recover for 3 days. We observed a significant pulmonary and neurological immune response to DE characterized by the development of inducible bronchus associated lymphoid tissue in the lung and gliosis in the frontal areas of the brain. We also observed that IL-22 knock-out increased pulmonary and neurological inflammation severity. Animals exposed to DE and treated with AT-RvD1 displayed reduced lung pathology severity and gliosis. Our data demonstrate that DE exposure contributes to neurological inflammation and that IL-22 is crucial to effective tissue repair processes. Our data further suggest that AT-RvD1 may have potential as a novel therapeutic for organic dust exposure-induced, immune-mediated pulmonary and neurological inflammation, improving outcomes of those with these diseases.

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by stenosis or occlusion of the internal carotid artery, thus leading to ischaemic and haemorrhagic strokes. Although genetic studies have identified ring finger protein 213 (RNF213) as a susceptibility gene, the low disease penetrance suggests that a secondary trigger, such as infection, may initiate disease onset. This study aimed to characterize the innate immune cell profile of peripheral blood mononuclear cells (PBMCs) of MMD patients via mass cytometry (CyTOF). Blood samples from 10 MMD patients and 10 healthy controls were analysed, with a focus on natural killer (NK) cells, monocytes, and dendritic cells (DCs). The results revealed significant changes in the NK and monocyte subpopulations in MMD patients; specifically, there was a decrease in the CD56dimCD16- NK03 subset and an increase in CD163high classical monocytes, thus indicating compromised microbial defences and heightened inflammation. Additionally, significant changes were observed in DC subpopulations, including an increase in CCR7+ mature DCs and a decrease in CD141+ and CD1c+ DCs. Overactivation of the TLR/MyD88/NF-κB pathway was observed in most innate immune cells, thus indicating its potential role in disease progression. These findings provide novel insights into immune dysfunction in MMD and highlight potential therapeutic targets.

Mushroom-forming fungi frequently encounter competitors during their lifecycle, but their defense mechanisms remain largely unexplored. We studied the response of the mushroom-forming fungus Schizophyllum commune during interaction with the fungal competitors Trichoderma harzianum, Trichoderma aggressivum and Purpureocillium lilacinum and the bacterial competitor Serratia quinivorans. Transcriptomics revealed 632 up-regulated genes in the direct interaction zone, which were enriched in small secreted proteins and transporters. A set of 26 genes were up-regulated during all interactions, indicating a core transcriptomic defense response. In the non-interacting edge of the mycelium of S. commune, there were 154 up-regulated genes, suggesting that there is a systemic response due to a signal that reaches unaffected areas. The GATA zinc finger transcription factor gene gat1 was up-regulated during interaction and a Δgat1 strain displayed increased colonization by T. harzianum. Previously linked to mushroom development, this transcription factor apparently has a dual role. Moreover, 138 genes were up-regulated during both interaction and mushroom development, indicating priming of the defense response during development to prepare the fruiting body for future interactions. Overall, we unveiled a defensive response of S. commune during interaction with fungal and bacterial competitors and identified a regulator of this response.

The immune system is crucial for organisms to defend against pathogens. Likewise, analogous immune features evolved against similar pressures at the superorganism scale. Upregulating hygiene to the same fungus pathogen is one assumption for convergent immune mechanisms in social insects, although more evidence of immune memory features remains to be confirmed. Here, we assess immune memory traits at the colony level in the leaf-cutting ant Atta sexdens. We exposed their fungus cultivar to both homologous and heterologous challenges with the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana, as well as the mycoantagonistic fungi Fusarium oxysporum and Trichoderma spirale. By measuring ants' behaviours, we evaluated the capacity of A. sexdens: (i) to enhance their collective hygiene, (ii) speed their hygiene in further infections, (iii) how long this capacity lasts in the colonies and (iv) the degree of specificity to increase hygienic responses. Fungus grooming behaviour was enhanced mostly against entomopathogenic fungi, with a trend of faster reactions during homologous challenges. In general, the capacity to elicit such upregulated actions lasted for up to 30 days, but no longer than 60 days. Overall, colonies exhibited a degree of immune specificity, enhancing hygiene only in response to homologous exposures but decreasing it when infected secondarily with a different fungus, indicating flexible social immunity of A. sexdens after immune challenges.

Recent advancements in medical management, endoscopic sinus surgery, and biologics have significantly improved outcomes for patients with chronic rhinosinusitis (CRS). However, long-term recurrence is frequently observed following endoscopic sinus surgery, with symptoms worsening after biologics are discontinued. Consequently, refractory or recurrent CRS remains a significant challenge, causing a substantial healthcare burden. In this review, we provide current insights into mucosal inflammatory memory, a potential mechanism leading to CRS recurrence. Given that both immune and non-immune cells in the sinonasal mucosa play critical roles in the pathophysiology of CRS, a deeper understanding of the mechanisms underlying mucosal inflammatory memory in various cellular components of sinonasal tissue could aid in the management of refractory CRS. We describe and discuss the latest knowledge regarding the novel concept of inflammatory memory, including both adaptive immune memory and trained immunity. Additionally, we summarize the pathogenic memory features of the sinonasal mucosa cellular components in the context of CRS.

Melanin is an essential product that plays an important role in innate immunity in a variety of organisms across the animal kingdom. Melanin synthesis is performed by many organisms using the tyrosine metabolism pathway, a general pathway that utilizes a type-three copper oxidase protein, called PO-candidates (phenoloxidase candidates). While melanin synthesis is well-characterized in organisms like arthropods and humans, it is not as well-understood in non-model organisms such as cnidarians. With the rising anthropomorphic climate change influence on marine ecosystems, cnidarians, specifically corals, are under an increased threat of bleaching and disease. Understanding innate immune pathways, such as melanin synthesis, is vital for gaining insights into how corals may be able to fight these threats. In this study, we use comparative bioinformatic approaches to provide a comprehensive analysis of genes involved in tyrosine-mediated melanin synthesis in cnidarians. Eighteen PO-candidates representing five phyla were studied to identify their evolutionary relationship. Cnidarian species were most similar to chordates due to domain presents in the amino acid sequences. From there, functionally conserved domains in coral proteins were identified in a coral disease dataset. Five stony corals exposed to stony coral tissue loss disease were leveraged to identify 18 putative tyrosine metabolism genes, genes with functionally conserved domains to their Homo sapiens counterpart. To put this pathway in the context of coral health, putative genes were correlated to melanin concentration from tissues of stony coral species in the disease exposure dataset. In this study, tyrosinase was identified in stony corals as correlated to melanin concentrations and likely plays a key role in immunity as a resistance trait. In addition, stony coral genes were assigned to all modules within the tyrosine metabolism pathway, indicating an evolutionary conservation of this pathway across phyla. Overall, this study provides a comprehensive analysis of the genes involved in tyrosine-mediated melanin synthesis in cnidarians.

From the start of life on Earth, several immune defense mechanisms have evolved to guarantee cellular integrity, homeostasis, and host survival. All these sophisticated balances as shaped by and towards the environmental needs have occurred over hundreds of millions of years. Human spaceflight involves various health hazards, such as higher levels of radiation, altered gravity, isolation and confinement, living in tight quarters, and stress associated with being away from home. A growing body of evidence points towards immunological changes in astronauts, including heightened pro-inflammatory responses, reactivation of latent viruses, and cell-mediated alterations, reflecting a dysbalanced state in astronauts. Simultaneously, enhanced pathogenicity, virulence, and drug resistance properties of microorganisms tip the scale out of favor for prolonged stay in space. As we have learned from the past, we see potential for the human immune system, forged and maintained throughout evolutionary history, to adapt to the space exposome. It is unlikely that this will happen in the short time frames set for current space exploration missions. Instead, major risks to astronaut health need to be addressed first, before humans can safely evolve into the space environment.

Interstitial lung disease (ILD) is one of the significant complications of dermatomyositis (DM), but the mechanisms by which it occurs remain incompletely elucidated. This study aimed to explore further the possible genetic mechanisms by which this complication occurs.

Gene expression profiles for DM (GSE39454, GSE46239, GSE143323) and ILD (GSE32537, GSE110147, GSE150910) were downloaded from the Gene Expression Omnibus (GEO) database. After identifying common differentially expressed genes (DEGs) to DM and ILD using the "limma" R package and the "VennDiagram" R package, functional annotation, relationship to immune cell infiltration, identification of transcription factors (TFs), we also collected clinical cases of DM-associated ILD (DM-ILD), including 3 cases of rapidly progressive ILD (RP-ILD) and 3 cases of none-RP-ILD, and explored whether there were differences in serum lymphocyte subpopulations.

A total of 4 common DEGs (SLAMF7, SPP1, TDO2, and VCAM1) were screened and Gene Ontology (GO) enrichment analysis showed that these genes were mainly enriched in T cell activation, regulation of lymphocyte activation, lymphocyte differentiation, leukocyte proliferation and regulation of T cell activation. In terms of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, the three significantly enriched pathways were the PI3K-Akt signaling pathway, MAPK signaling pathway, and Cytokine-cytokine receptor interaction. In lung and muscle tissues, 21 and 3 TFs may regulate the expression of these genes, respectively. Finally, by analysing the serum lymphocyte subpopulations, we also found a decrease in the absolute number of CD8+ T cells and an increase in the CD4+ /CD8+ T cell ratio in DM combined with RP-ILD.

These common pathways and key genes may provide new ideas for further research into DM-ILD.

Background/Objectives: Antimicrobial peptides are essential molecules in the innate immunity of various organisms and possess a broad spectrum of antimicrobial, antitumor, and immunomodulatory activities. Due to their multifunctionality, they are seen as an alternative for controlling bacterial infections. Although conventional antibiotics have improved health worldwide, their indiscriminate use has led to the emergence of resistant microorganisms. To discover new molecules with antimicrobial activity that could overcome the limitations of traditional antibiotics, this study aimed to identify antimicrobial peptides in Ambystoma mexicanum. Methods: In this study, hypothetical proteins encoded in the Ambystoma mexicanum transcriptome were predicted. These proteins were aligned with peptides reported in the Antimicrobial Peptide Database (APD3) using the Fasta36 program. After identifying peptide sequences with potential antibacterial activity, their expression was confirmed through conventional polymerase chain reaction (PCR) and then chemically synthesized. The antibacterial activity of the synthesized peptides was evaluated against Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922. Results: A new antimicrobial peptide named AXOTL-13 was identified. AXOTL-13 is an amphipathic cationic alpha-helical peptide with the ability to inhibit the growth of Escherichia coli without causing hemolysis in red blood cells, with its action likely directed at the membrane, as suggested by morphological changes observed through scanning electron microscopy. Conclusions: This research is pioneering in evaluating the activity of antimicrobial peptides present in Ambystoma mexicanum and in specifically identifying one of these peptides. The findings will serve as a reference for future research in this field.

During the past decade, compelling evidence has accumulated demonstrating that innate immune cells can mount adaptive characteristics, leading to long-term changes in their function. This de facto innate immune memory has been termed trained immunity. Trained immunity, which is mediated through extensive metabolic rewiring and epigenetic modifications, has important effects in human diseases. Although the upregulation of trained immunity by certain vaccines provides heterologous protection against infections, the inappropriate activation of trained immunity by endogenous stimuli contributes to the pathogenesis of inflammatory and neurodegenerative disorders. Development of vaccines that can induce both classical adaptive immunity and trained immunity may lead to a new generation of vaccines with increased efficacy. Activation of trained immunity can also lead to novel strategies for the treatment of cancer, whereas modulation of trained immunity can provide new approaches to the treatment of inflammatory diseases.

Human tissue-resident memory T (TRM) cells play a crucial role in protecting the body from infections and cancers. Recent research observed increased numbers of TRM cells in the lung tissues of idiopathic pulmonary fibrosis patients. However, the functional consequences of TRM cells in pulmonary fibrosis remain unclear. Here, we found that the numbers of TRM cells, especially the CD8+ subset, were increased in the mouse lung with bleomycin-induced pulmonary fibrosis. Increasing or decreasing CD8+ TRM cells in mouse lungs accordingly altered the severity of fibrosis. In addition, the adoptive transfer of CD8+ T cells containing a large number of CD8+ TRM cells from fibrotic lungs was sufficient to induce pulmonary fibrosis in control mice. Treatment with chemokine CC-motif ligand (CCL18) induced CD8+ TRM cell expansion and exacerbated fibrosis, whereas blocking C-C chemokine receptor 8 (CCR8) prevented CD8+ TRM recruitment and inhibited pulmonary fibrosis. In conclusion, CD8+ TRM cells are essential for bleomycin-induced pulmonary fibrosis, and targeting CCL18/CCR8/CD8+ TRM cells may be a potential therapeutic approach. NEW & NOTEWORTHY The role of CD8+ TRM cells in the development of pulmonary fibrosis was validated and studied in the classic model of pulmonary fibrosis. It was proposed for the first time that CCL18 has a chemotactic effect on CD8+ TRM cells, thereby exacerbating pulmonary fibrosis.

An in-depth understanding of the immune system of endangered species is crucial for successful conservation efforts. Galectins, as members of the lectin family, play a crucial role in the fish innate immune system. Galectin-9 (Tfgal-9) was cloned from endangered species Trachidermus fasciatus, revealing a cDNA sequence of 1453 bp with an open reading frame of 900 bp encoding a protein of 299 amino acids. Tfgal-9 protein features two repeated carbohydrate-binding domains, each characterized by two conserved galactose-binding sites (H-NPR and WG-EER), and it possesses neither a signal peptide nor a transmembrane domain. The qRT-PCR analysis revealed that Tfgal-9 was widely expressed across all examined tissues, with the highest expression in the intestine, followed by the blood, heart and brain. Expression was notably up-regulated in the blood, skin, liver, stomach, and heart when challenged with LPS. Following induction by the heavy metal solution containing Cu, Pb, Cd, and Hg, the expression Tfgal-9 was dramatically induced to 32 times higher than that of the control group in the brain. The recombinant Tfgal-9 protein exhibits calcium-independent binding and agglutination of selected bacteria and yeast. Antimicrobial activity of recombinant Tfgal-9 protein against Gram positive bacteria Staphylococcus aureus was confirmed using the cylinder-plate method. In vitro antioxidant experiments showed that radical scavenging activity of DPPH was 50.38 % when Tfgal-9 concentration reached 200 μg/mL. These results indicate that Tfgal-9 may play important roles in the immune response against microbial infections and the maintaining of redox homeostasis.

The immune system of newborns is underdeveloped, leaving them susceptible to infections like rotavirus (RV). Despite vaccines, RV remains a leading cause of child mortality, especially in developing countries. Maternal immunity is transferred during pregnancy and breastfeeding to the offspring providing protection against RV infection. This study aims to explore how the maternal diet can enhance the newborn's ability to fight early infections. Pregnant rats received orally Bifidobacterium breve M-16 V and short chain galacto-oligosaccharides (scGOS)/long chain fructo-oligosaccharides (lcFOS). At day 5 of life pups are infected with RV and at day 8, samples are collected for the infection analysis. Pups whose mothers received the synbiotic have lower RV infection severity. The levels of immunoglobulins (Ig) IgG2c and IgA are raised in pups' plasma and digested milk, respectively. Synbiotic supplementation improves intestinal maturation and increases gene expression of immune-related genes. In conclusion, the administration of this synbiotic to gestating and lactating mothers ameliorates the incidence and severity of the pup's diarrhea caused by the RV infection by improving their immunity.